Alzheimer's Disease (AD) is an age-related neurological disorder that affects almost exclusively associational areas of the human brain resulting in senile dementia. AD has been characterized neuropathologically by the presence of neurofibrillary tangles, neuritic plaques, and neuronal cell loss in specific cortical and subcortical brain regions. While these are the most characteristic features of this disease, evidence from clinico- pathological studies indicate a rather poor correlation between the occurrence of these pathologies and the severity of dementia. At present a decrease in synaptic density provides the best correlation to cognitive dysfunction in AD. The mechanisms mediating synaptic loss in AD are unknown. It is unclear, for example whether this is due to changes in the postsynaptic neuron and its ability to perceive changes in synaptic activity or whether a combination of pre- and post-synaptic events are required. A better understanding of the molecular mechanisms that regulate the stability of synapses or their dynamics behavior would contribute greatly to our understanding of the neuropathology of AD and consequently to the understanding of the behavioral abnormalities associated with this illness. This proposal focuses on investigating specific hypotheses concerning the possible functional roles three novel synaptic junctional proteins, SAP90, SAP97 and SAP102, may play in modulating the assembly state of synapses in AD. The primary goal of this proposal is to utilize biochemical, molecular, cell biological and immunohistochemical techniques to examine what roles SAP90, SAP97 and SAP102 perform in synaptic junctions. Our comprehensive working hypothesis is that the synaptic associated guanylate kinases (GKs) are involved in modulating the release of neurotransmitter (Nt) via second messenger systems, which may also regulate the efficiency and stability of synaptic junctions. Dysfunctional modifications of these GKs may contribute to the etiology of AD and other neurodegenerative diseases by altering synaptic stability. The first goal of this proposal is to examine whether SAP90, SAP97 and SAP102 are required for t he formation and maintenance of synaptic junctions. The second goal is to determine whether members of this family encode authentic guanylate kinases. The third goal is to test whether SAPs at synaptic junctions possess a GK activity that is modulated by synaptic activity. The final goal is to determine whether SAPs are differentially expressed in aging and in Alzheimer's brain.